Microneedle and chip

ABSTRACT

A microneedle and a chip are disclosed for extraction fluids. The microneedle is provided on a substrate and comprises an elongated body extending from a distal end with a bevel to a proximal end on the substrate along a longitudinal axis. The elongated body comprises a capillary bore extending in a longitudinal direction thereof and defines a fluid path. The proximal end is integrally connected with the substrate and the capillary bore is in fluid communication with a fluid channel of the substrate. The cross-sectional area of the capillary bore in the distal end is larger than the cross-sectional area of the capillary bore in the proximal end.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 15/579,135, filed Dec. 1,2017, which is a 371 National Stage of PCT/SE2016/051211, filed Dec. 2,2016, which claims foreign priority to Swedish Application No.1530184-9, filed Dec. 4, 2015, the disclosures of which are incorporatedby reference.

TECHNICAL FIELD

The present invention relates in general to a microneedle and a chip forsampling of bodily fluids. The present invention relates in particularto microneedles provided on a substrate. The microneedle comprises anelongated body extending from a distal end with a bevel to a proximalend on the substrate along a longitudinal axis, and the elongated bodycomprises a capillary bore extending in a longitudinal direction thereofand defines a fluid path, and the proximal end is connected to thesubstrate, and the capillary bore is in fluid communication with a fluidchannel of the substrate.

BACKGROUND

Although many application fields exist for microneedles, the vastmajority of published microneedles concern drug delivery in variousfarms. The concept of an array of miniaturized needles for drug deliverypurposes dates back to the 70's—see U.S. Pat. No. 3,964,482, One of theearliest reported microneedles in the scientific literature was anout-of-plane silicon needle array featuring 100, 1.5 mm long, needles onan area of 4.2 mm×4.2 mm in P. K. Campbell, “A Silicon-Based,Three-Dimensional Neural Interface: Manufacturing Processes For AnIntercortical Electrode Array”, IEEE Trans Biomed Eng., Vol. 38, No. 8,August 1991, pp. 758-68. Eventually, bio sensing technology will be tothe 21st century what microelectronics was to the second half of the20th century.

Integrated circuits (IC) have had an enormous impact on our daily lifetoday and making use of the same miniaturization and cost benefits ofvolume manufacturing bio sensing might move clinical diagnosis andhealth monitoring from expensive laboratories to small hand-heldconsumer devices. Sampling of an analyte to be measured is aprerequisite for bio sensing. Many of the designs described inscientific papers have the purpose of extracting bodily fluids i.e.blood or interstitial fluid, ISF. Successful extraction of blood hasbeen demonstrated with use of the natural “overpressure” in the vascularsystem. However, successful extraction of ISF without under-pressure,through diffusion or other mechanisms are rare or even non-existing.

SUMMARY OF THE INVENTION

The aim of the present invention is to set aside the abovementioneddrawbacks and shortcomings of the previously known microneedles and toprovide an improved solution. An object of the invention is to providean improved microneedle of the initially defined type which allows easysampling of interstitial fluid, ISF.

The object of the invention is met in a microneedle and a chiprespectively as defined in the appending claims.

In a first aspect, the present invention relates to a microneedleprovided on a substrate, comprising: an elongated body extending from adistal end with a bevel to a proximal end on the substrate along alongitudinal axis; the elongated body comprises a capillary boreextending in a longitudinal direction thereof and defines a fluid path,the proximal end is integrally connected with the substrate and thecapillary bore is in fluid communication with a fluid channel of thesubstrate; wherein the cross-sectional area of the capillary bore in thedistal end is larger than the cross-sectional area of the capillary borein the proximal end. A bevel is referred to as a bevelled surfacerelative the longitudinal axis of the capillary bore.

In a second aspect, the present invention relates to a chip, comprising:a plurality of microneedles integrally formed on a substrate, eachmicroneedle comprising: an elongated body extending from a distal endwith a bevel to a proximal end on the substrate along a longitudinalaxis; the elongated body comprises a capillary bore extending in alongitudinal direction thereof and defines a fluid path, wherein across-sectional area of the capillary bore in the distal end is largerthan the cross-sectional area of the capillary bore in the proximal end;the proximal end is integrally formed with the substrate and the firstfluid path is in fluid communication with a fluid channel of thesubstrate; and the substrate having a fluid channel which forms a fluidpath, wherein the fluid channel has a width larger than the depth of thefluid channel.

Additional or alternative features of the first aspect are describedbelow.

The cross-sectional area of the capillary bore of the microneedle maygradually decrease from the distal end towards the proximal end alongthe longitudinal direction. This contributes to an enhanced fluid flowthrough the capillary bore, by means of capillary three acting on thefluid in the capillary bore. The cross-section (crosswise to thelongitudinal direction) of the capillary bore may further comprise atleast one rounded corner. This contributes to the wetting of thecapillary bore, which has a positive effect on the fluid flow.

The capillary bore may have a triangular cross-section. A triangularcross-section has been demonstrated to provide a very good fluid flow inthe capillary bore. A triangular cross-section within this applicationencompasses cross sections with substantially triangular shape, i.e.edges with convex or concave shape or straight shape, corners with sharpangles and corners with blunt angles as well as rounded corners.

The walls of the capillary bore may comprise hydrophilic surfaces, whichenhances the fluid flow in the capillary bore.

The fluid channel may be configured to provide an under-pressure,relative the atmospheric pressure, to the capillary bore, whereby fluidflow through the capillary bore is enhanced. An under-pressure may furexample be created with a syringe connected to the fluid channel. Theelongated body of the microneedle may further comprise a lateral holeextending in a radial direction relative the longitudinal direction,wherein the lateral hole is in fluid communication with the capillarybore. This has the effect that the risk for clogging in the capillarybore is reduced.

Below, alternative or additional features of the second aspect arepresented.

In a chip, wherein at least a part of a wall of the capillary bore mayform a part of a wall of the fluid channel, fluid flow is enhanced.

The fluid channel of a chip may comprise directional changes with anangle Θ smaller than 90 degrees. By avoiding sharp bends of the fluidchannel, fluid flow is enhanced. The chip may further comprise a basesubstrate, which comprises a fluid port in fluid communication with thefluid channel, and which opens in the backside of the base substrate.This provides an access point to the sampled fluid which can beconnected to a sensor element or further fluid channels. The fluid portmay comprise an increasing area in the longitudinal direction of theport towards the back of the base substrate. This allows a fluid tightconnection to other fluid channels such as tubes or syringes.

The base substrate may be operatively connected to the substrate bymeans of anodic/direct bonding, which provides a strong and fluid tightseal without the risk of clogging the fluid channels with adhesive.

The plurality of microneedles on the chip may be surrounded by an edge,which is in level with the distal end of the microneedles. This has theeffect that a membrane of a test subject is tensioned during engagementwith the distal end of the microneedles.

BRIEF DESCRIPTION OF THE DRAWINGS

A more thorough understanding of the abovementioned and other featuresand advantages of the present invention will be evident from thefollowing detailed description of embodiments with reference to theenclosed drawings, in which:

FIG. 1 is a schematic perspective view of a chip with a plurality ofmicroneedles;

FIG. 2 is a schematic top view of a chip with a plurality ofmicroneedles;

FIG. 3 is a bottom view of a substrate with fluid channels;

FIG. 4 is cross-sectional view along the line C-C in FIG. 2;

FIG. 5 is a cross-sectional view of a microneedle;

FIG. 6 is a cross-sectional view along the longitudinal axis of amicroneedle;

FIG. 7 is a bottom view of the substrate with fluid channels;

FIG. 8 is a schematic perspective view of the microneedles on thesubstrate; and

FIG. 9 is a schematic perspective view of the backside of the substratewith fluid channels and capillary bores.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The present invention is based on the insights below. When examinedcarefully, it is clear that the microneedles in the prior art eithercannot be manufactured with good yield, they are not robust enough toallow for safe use in mammals or the actual extraction is performed withseveral caveats described in the smallest possible font. Examples ofcaveats and disclaimers described in prior art are for instance thatextraction only has been demonstrated on pig skin, on mammals withblisters in controlled studies or with the outmost skin layer, stratumcorneum, removed prior to extraction. It's therefore safe to say that itwas utterly surprising that a robust, volume manufacturable design ofmicroneedles could be invented, designed and realized allowing for safeextraction where the extraction is performed using only capillary forcesand no sub pressure or suction.

According to certain embodiments of the invention, the invention regardsa design of a Microneedle chipset comprising a plurality of needlesorganized in an array or matrix at a minimum distance from each other of100 micrometers but not greater than 1 mm apart, has a sharp tip in thesame plane or slightly below a surrounding structure and where the tiphas a 54.7 degree bevel and the needle a hollow bore with a capillarydimension that allows extraction without clogging and a shaft, longerthan 200 micrometers as well as interior dimensions and geometry thatallow capillary forces to act on liquid all the way to the collectingchannels/voids/cavities where misaligned holes in backside channelsconnect.

According to some embodiments of the invention, the invention ischaracterized by a chipset with the above described plurality ofmicroneedles where:

-   -   The needles have a sharp tip defined by crystallographic planes.    -   The bevel slope of each needle is defined by the 111 planes.    -   Each microneedle may comprise a capillary bore, e.g. a single        capillary bore.    -   Thereby bodily fluid may be extracted by means of capillary        suction through the microneedle, fluid cavity and fluid exit        port.    -   Each microneedle may be provided with a cap at a distal end for        shielding the capillary bore from clogging, whereby at least one        opening to the capillary bore is provided in a lateral direction        of the microneedle, perpendicular to the axial or longitudinal        extension of the microneedle. The capillary bore of each        microneedle may be provided with a hydrophilic surface. Thereby        capillary flow of bodily fluid may be assisted.    -   Each microneedle may comprise a plurality of cutting elements        extending along a longitudinal direction of the microneedle.        Thereby the skin may be cut and opened to facilitate extraction        of bodily fluid.    -   The perimeter of the bore hole in each microneedle as projected        on the bevel of the needle is located at a distance from the tip        in a way where the tip is outside the perimeter.    -   Each microneedle may have a length of 200-1000 μm, preferably        400-900 μm, more preferably 300-600 μm, and an outer        circumference of 400-800 μm. Thereby, the microneedle has        dimensions suitable for penetration of the skin and extraction        of bodily fluid.    -   A portion of the bore hole as projected on the side that        contains the capillary system is outside the connecting        capillary generating a maximized wall surface that minimizes        surface tension.    -   Each connection between the bore hole and the capillary should        be designed with a minimized contact angle in order to enable        tension driven flow.    -   Surfaces in contact with the fluid should be hydrophilic    -   The shaft of each needle is without a hilt    -   The vertical bore holes may be filled with material that is        selective and specific to certain molecules and thereby creating        an integrated extraction and sensing chipset. The filler        material could for instance be glucose oxidase and carbon powder        and thereby creating a glucose specific extraction and sensing        chipset.    -   A plurality of openings may be provided in a lateral direction,        around a circumference of the microneedle. The at least one        opening may be provided about midways along a longitudinal        extension of the microneedle. Thereby, the extraction of bodily        fluid is facilitated and the risk for clogging is further        reduced.

According to some embodiments of the invention, the invention is furthercharacterized by the above described chipset where the plurality ofneedles:

-   -   Have a frame structure dimensioned to support the tip of a        finger constructed as structure protruding along the        longitudinal direction of the microneedles, and preferably        having a diameter of less than 15 mm.    -   May be at least partly surrounded by a frame structure        dimensioned to support the tip of a finger. Thereby the skin of        the tip of the finger may be supported and tensioned to        facilitate penetration of the at least one microneedle into the        skin.    -   Are protected by a surrounding structure protruding to at least        the same plane as the tip of the needles enabling for instance        handling of wafers in the case of MEMS manufacturing of the        herein described chipset.    -   Have a surrounding structure that stretches the skin prior to        penetration by the above-mentioned plurality of needles.    -   With their hollow structure constitute inlets for sampling of        bodily fluid. Thereby bodily fluid, such as interstitial fluid        (ISF) may be extracted and introduced into a sensor with minimal        discomfort for the patient.    -   Have the collecting network of capillaries in different patterns        and as an    -   advantage is collection of liquid and storage made without        evaporation problems. Hence, the chip can sample and the        analysis can be made ex situ.    -   Have the interface between the vertical bore holes and the        collecting capillary laterally misaligned to allow liquid to wet        the walls and hence by capillary action fill the collecting        channels on the backside.    -   Are located at minimum distance from each other of 200 microns        in order to avoid the effect of bed of nails.    -   Have the bevel oriented in the crystallographic directions or        preferred in the same direction.    -   Are oriented in a way that enables connection between at least a        subset of needles using integrated, for instance etched,        capillaries.    -   Could all be combined with a capillary system enabling a        capillary flow to a fluid exit port.

Configurations

-   -   In another configuration, the above described sampling chipset        may be used in conjunction with a sensing unit. The sensing unit        may be wafer bonded or attached to the extraction chipset by        other means but may also be connected through capillary tubing        or an equivalent flow system.    -   The sensing unit may be configured for detecting a level of        glucose in bodily fluid, i.e. a glucose sensor. Thereby a sensor        for rapid and accurate detection of the level of glucose in        bodily fluid may be provided.    -   The sensor may be configured for detecting a concentration or        presence of lactate, carbon dioxide, or other molecules in        bodily fluid. Thereby a sensor for rapid and accurate detection        of the level of above-mentioned molecule or other molecules,        ions or biomarkers in bodily fluid may be provided.

In a first embodiment of the present invention, a chip, generallydesignated 115, is shown in a perspective view in FIG. 1. The chip 115comprises a substrate 102 with a plurality of microneedles 101 arrangedthereon. Each of the microneedles comprises a capillary bore 107, whichextends through the microneedle and the substrate 102. In the aboveparagraphs the capillary bore 107 is denoted vertical hole. Thesubstrate 102 further comprises a surrounding wall 112 with an upperedge 117. The upper edge 117 may have the same height as themicroneedles. This proves to be very useful if a finger of a testsubject is supposed to interact with the microneedles, since atensioning effect of the skin is achieved.

In FIG. 2, the chip of FIG. 1 is shown from above. This view shows thearrangement of the microneedles 101 on the substrate 102. Themicroneedles 101 are preferably arranged with a minimum distance, A andB, of 200 μm between neighboring microneedles in order to avoid the bedof nails effect. However, the distance between neighboring microneedlesmay be in the interval from 100 μm to 1 mm. In this view, a line C-C isalso illustrated, and this imaginary line will be used later to define across section through the substrate and the microneedles. In FIG. 3, apattern of fluid channels 309 which provides fluid communication betweenthe microneedles is illustrated. This figure is a view from the backsideof the substrate 102. In this view, the capillary bores 107 of themicroneedles are shown and opens into the fluid channels 309 of thesubstrate 102. The fluid channels 309 are shallow with a width thatpreferably is larger than a corresponding depth. The fluid channels maycomprise a decreasing cross-sectional area in order to further enhancethe fluid flow in the fluid channel (not illustrated). The fluidchannels are arranged in spiral pattern around a fluid channel port 318.In one embodiment the pattern of fluid channels may comprise aperipheral flow path which connects capillary bores of the peripheralmicroneedles (not illustrated). This has the effect that even if a fluidchannel 309 is clogged, fluid is allowed to flow to the fluid channelport 318.

FIG. 4 is a cross sectional view along the imaginary line C-C through arow of microneedles and the substrate 102. Thus, the substrate is cutopen and viewed from a side view. In this figure, a microneedle 101 isshown cut open. The microneedle comprises a bevel 505 defined bycrystallographic planes of the material of the microneedle. Thecapillary bore 507 is in fluid communication with the fluid channel port318 and the fluid channel 309. The substrate 102 is operativelyconnected to a base substrate 413, which comprises a fluid port 414. Thefluid port 414 may comprise sloped sidewalk, which provides an easy andfluid tight connection to other devices. The base substrate 413 may beoperatively connected to the substrate 102 by means of bonding, forexample anodic or direct bonding, which are well known in the art.

The microneedle 101 is further illustrated in FIG. 5 in which amicroneedle is cut open. The microneedle 101 comprises an elongated body503 with a distal end 504 and a proximal end 506 on the substrate 102.In this embodiment the microneedle is integrally formed from thesubstrate. Such a manufacturing process may involve the followingprocess steps:

-   -   Define the elongated body 503 by means of photolithography, PL,        and dry etching of the substrate 102, using for example Deep        Reactive-Ion Etching, DRIE.    -   Define the bevel 505 of the distal end 504 using anisotropic wet        etching. Define the mask for the capillary bore 507, by means of        applying photoresist on the substrate 102, followed by PL which        defines a mask with an opening on the bevel 505.    -   Etching of the capillary bore 507 from the front side of the        substrate 102 through the mask opening on the bevel 505.

In the exemplary process outlined above, the photo resist applied to thesubstrate 102 may be spray coating resist or dry film resist. The bevel505 of the distal end 504 provides a sharp edge particularly suitablefor bio sensing applications. The capillary bore 507 opens in the bevel505 such that a distance between the periphery of the capillary bore 507and the tip of the sharp edge of the bevel is obtained. The capillarybore 507 extends from the bevel 505 of the distal end 504 of theelongated body 503 towards the proximal end 506 on the substrate 102.The cross-sectional area of the capillary bore in the distal end 504 islarger than the cross-sectional area of the capillary bore 507 in theproximal end 506. This way, capillary action is enhanced and the fluidflow through the capillary bore 507 increases.

An embodiment of the microneedle 101 is shown from above in FIG. 6. Inthis figure, the triangular cross-section 610 of the capillary bore 507is shown. In this application a triangular cross-section shouldencompass a shape with three edges connected with corresponding corners.The edges may be straight, curved, convex or concave. The corners may besharp, blunt or rounded with different or the same radius. Thus, withinthis application a cross-section with the shape of an egg or a heart isconsidered to be triangular. The triangular shape of the capillary bore610. In FIG. 6, the shape of the capillary bore 507 is substantiallytriangular with a convex base connected to straight sections via acurved corner 611. This shape of the capillary bore 507 has beendemonstrated to be very efficient for extracting interstitial fluid froma finger of a human test subject.

In FIG. 7, a magnified view of the backside of the substrate 102 isshown. The fluid channel port 318 of the backside of the substrate 102is connected to a number of fluid channels 309. In this figure, thewidth of the fluid channel 309 is designated W and the curved angle isdesignated Θ. In order to provide a tension driven fluid flow, themaximum curved angle is 90 degrees. The capillary bores 507 are alsoconnected to the fluid channels 309 such that at least a part of a wall916 of the capillary bore forms a part of a wall of the fluid channel309. This is further illustrated in FIG. 9.

Finally, FIG. 8 illustrates that the distal end of the microneedles 101are in level with the upper edge 1 17. This edge provides a tensioningeffect of the skin upon contact between the skin and the chip.

Additional features that are disclosed in relation to the firstembodiment can also be applied to the second embodiment.

In one embodiment, the substrate 102 made of silicon, and the basesubstrate 413 is made of glass.

The claims attached are drafted to define the scope of inventionincluding the embodiments disclosed and modifications andimplementations thereof which can be derived from the disclosure.

1. A microneedle provided on a substrate, comprising: an elongated bodyextending from a distal end thereof with a bevel to a proximal end onthe substrate along a longitudinal axis, wherein: the elongated bodycomprises a capillary bore extending in a longitudinal direction thereofand defines a fluid path; the proximal end is connected to the substrateand the capillary bore is in fluid communication with a fluid channel ofthe substrate; wherein the cross-sectional area of the capillary borecomprises a triangular cross-section in a perpendicular directionrelative the longitudinal direction of the microneedle.
 2. A microneedleaccording to claim 1, wherein the triangular cross-section of thecapillary bore further comprises at least one rounded corner.
 3. Amicroneedle according to claim 1, wherein the triangular cross-sectionof the capillary bore comprises a convex base connected to straightsections via two rounded corners.
 4. A microneedle according to claim 1,wherein the capillary bore comprises a hydrophilic surface.
 5. Amicroneedle according to claim 1, wherein the fluid channel isconfigured to provide an under-pressure, relative the atmosphericpressure, to the capillary bore, whereby fluid flow through thecapillary bore is promoted.
 6. A microneedle according to claim 1,wherein the elongated body further comprises a lateral hole from a sideof the microneedle and extends in a radial direction relative thelongitudinal direction, wherein the lateral hole is in fluidcommunication with the capillary hole.
 7. A chip, comprising: aplurality of microneedles integrally formed on a substrate, eachmicroneedle comprising: an elongated body extending from a distal endthereof with a bevel to a proximal end thereof on the substrate along alongitudinal axis; wherein the elongated body comprises a capillary boreextending in a longitudinal direction thereof and defining a fluid path,wherein the cross-sectional area of the capillary bore comprises atriangular cross-section in a perpendicular direction relative thelongitudinal direction of the microneedle; and wherein the proximal endis integrally formed with the substrate and the first fluid path is influid communication with a fluid channel of the substrate.
 8. A chipaccording to claim 7, wherein the substrate comprises a fluid channelwhich forms a fluid path, wherein the fluid channel has a width largerthan the depth of the fluid channel.
 9. A chip according to claim 7,wherein at least a part of a wall of the capillary bore forms a part ofa wall of the fluid channel.
 10. A chip according to claim 7, whereinthe fluid channel comprises directional changes with an angle (Θ)smaller than 90 degrees.
 11. A chip according to claim 7, furthercomprising a base substrate, which comprises a fluid port in fluidcommunication with the fluid channel, and which opens in the backside ofthe base substrate.
 12. A chip according to claim 11, wherein the fluidport comprises an increasing area in the longitudinal direction of theport towards the back of the base substrate.
 13. A chip according toclaim 7, wherein the base substrate is operatively connected to thesubstrate by means of bonding.
 14. A chip according to claim 7, whereinthe plurality of microneedles are surrounded by an edge which is inlevel with the distal end of the microneedles.